Since Reed isolated α-lipoic acid from pork liver for the first time in 1950, the study of the physiological activity thereof deepens. α-lipoic acid belongs to vitamin drugs and is both lipid-soluble and water-soluble antioxidant, which can eliminate pathogenic radicals in vivo. It has been reported that α-lipoic acid can be used to treat radioactive damage, or diseases such as liver dysfunction and subacute necrotizing encephalomyelopathy. In China, α-lipoic acid is mainly used in the treatment of liver diseases such as acute hepatitis, hepatocirrhosis, and fatty liver. The physiological activity of α-lipoic acid is only limited to d-lipoic acid (i.e. (R)-α-lipoic acid), while (S)-α-lipoic acid substantially lacks physiological activities and other side-effects. Commercial optically pure (R)-α-lipoic acid is replacing racemic lipoic acid.
Current synthesis methods of (R)-α-lipoic acid are classified into chemical methods and biological ones. Elliott et al. conducted asymmetric synthesis of (R)-α-lipoic acid with a total yield of 37% by induction with chiral auxiliary reagents, but its strict reaction conditions and high cost of the reagents used limited its use in industry (Tetrahedron Letters, 1985, 26 (21): 2535-2538). Gopalan attempted to generate (R)-α-lipoic acid by catalysis with microbial enzymes, but the total yield was only 10% and the practicability thereof was poor (Journal of the Chemical Society, Perkin Trans., 1990, 7: 1897-1900). Recently, one of the well studied synthesis methods is enantio-separation which seperates racemic lipoic acid or its precursors with chiral resolving agents or esterases/lipases and converts them into (R)-α-lipoic acid. However, as (S)-α-lipoic acid is generated in the process at the same time, the theoretical highest yield is only 50%.
Alternatively, preparation of (R)-6-hydroxy-8-chlorocaprylate by enzymatic reduction is getting attention, but the yield and optical purity of the product thereof is not good in a few reports currently. For example, Olbrich et al. utilized the whole cell of Geotrichum candidum to catalyze the asymmetric reduction of 6-carbonyl-8-chlorocaprylate to generate (R)-6-hydroxy-8-chlorocaprylate, with a substrate concentration of 5 g/L, and after reaction for 24 h, the yield was only 62% and the ee value of the product was 88% (U.S. Pat. No. 7,135,328 B2). Müller et al. utilized the alcohol dehydrogenase TbADH from Thermoanaerobium brokii to catalyze the reductive conversion of 2 g/L of 6-carbonyl-8-chlorocaprylate to produce (R)-6-hydroxy-8-chlorocaprylate with an optical purity of 99.5%, but its conversion rate was only 85%, and it was necessary to add 0.5 mM coenzyme and 1 mM dithiothreitol (DTT) in the reaction system (U.S. Pat. No. 7,157,253 B2). Werner et al. utilized NgADH from Nocardia globulera to prepare (R)-6-hydroxy-8-chlorocaprylate, and the concentration of the substrate could be 44 g/L, but the ee value of the product thereof was not disclosed (WO 2007/028729 A1, 2007). Gupta et al. utilized an oxidoreductase from Metschnikowia zobellii to convert 85 g/L of the substrate 6-carbonyl-8-chlorocaprylate into the product (R)-6-hydroxy-8-chlorocaprylate, and it was necessary to add 0.1 mM coenzyme into the reaction system and the conversion rate after 24 h was only 55%, though the ee value of the product could get 97% (WO 2005049816 A2). To sum up, existing biological catalysts and their technical levels are far away from industrial application. For example, the carbonyl reductases reported so far generally have technical problems such as low catalytic activity, poor substrate tolerance, long reaction time, and undesired optical purity.
It can be seen that current synthesis methods of (R)-α-lipoic acid have various defects and are not able to meet the increasing demandment of optically pure (R)-α-lipoic acid. Therefore, there is still a need for improved synthesis methods of (R)-α-lipoic acid which meet the industrial requirement with high efficiency and low cost.